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The Bcl-2-associated death promoter (BAD) protein is a pro-apoptotic member of the Bcl-2 gene family which is involved in initiating apoptosis. Unlike most other members of the Bcl-2 family, BAD does not have a C-terminal transmembrane domain, which is a target of outer mitochondrial membrane and nuclear envelope. Upon activation, it forms a heterodimer with the anti-apoptotic proteins and prevents apoptosis.
TCTN1 Silencing Inhibits Proliferation of Thyroid Cancer by Increasing the Expression of BAD
The tectonic family member 1 (TCTN1) is a member of the tectonic family that regulates the hedgehog signaling pathway. There is a significant early and late apoptosis in thyroid cancer cells after TCTN1 knockdown, further demonstrating that TCTN1 plays a positive role in thyroid cancer cell growth and proliferation. The anti-apoptotic protein Bcl-2 plays a pivotal role in regulating cell apoptosis under many adverse conditions, while pro-apoptotic BAD is essential for inducing apoptosis. Recent studies have shown that silencing TCTN1 results in increasing BAD expression and reduced expression of Bcl-2. Collectively, inhibition of thyroid cancer cell proliferation induced by TCTN1 knockdown may be closely associated with cell cycle arrest and apoptosis in thyroid cancer cells.
BAD’s Mutation Contributes to GCK-MODY
Monogenic diabetes is a heterogeneous group of single-gene diabetes that result in β-cell dysfunction. Maturity onset diabetes of the young (MODY) is one of the major forms of monogenic diabetes recognized in the pediatric population. The GCK-MODY subtype, responsible for the majority of MODY cases in the pediatric population, is associated with the presence of heterozygous inactivating mutations in the glucokinase (GCK) gene. The GCK gene encodes an enzyme that plays a key role in regulating insulin secretion and hepatic glucose metabolism in beta cells. GCK gene expression is regulated at the transcriptional and posttranslational levels. By analysis the BAD gene sequence in patients with clinical suspicion of GCK-MODY but who are known to be negative for GCK gene mutations. As a result, an example in which a base pair substitution results in a non-synonymous replacement of an amino acid is found. Therefore, changes in the amino acid sequence of the BAD gene that regulates the activity of the GCK enzyme, may have an impact on the glucose metabolism in this patient.
Ursolic Acid Down-regulates the AKT/BAD Signaling Pathway
Oral squamous cell carcinoma (OSCC) is a type of cancer with high morbidity and mortality worldwide. In CAR cells treated with ursolic acid, the production of reactive oxygen species (ROS) and the loss of mitochondrial membrane potential were observed by flow cytometry. It was found that dephosphorylated BAD promoted apoptosis and inactivated other anti-apoptotic Bcl-2 family proteins, including Bcl-2, Bcl-xL and Bcl-w. The BAD protein is phosphorylated at serine 99 and serine 134 sites (serine 136 site in mice) by AKT, then the BAD protein dissociates from the heterodimer of Bcl-2/Bcl-xL and binds to a protein in the cytoplasm with an inactive form. Therefore, the free Bcl-2 and Bcl-xL can inhibit apoptosis. The apoptosis-associated signaling shows that ursolic acid decreases the phosphorylation of AKT (Ser473) and BAD (Ser136) and increases the expression of BAD and Bax protein in oral cancer cells.
Fig 1. An integrated model of the apoptosis-related signaling pathway induced by ursolic acid in human cisplatin-resistant oral cancer CAR cells (Chen et al. Oncology Reports.2018).